Breast and ovarian cancers are the second and fourth leading causes, respectively, of cancer deaths in females in the United States (American Cancer Society (2005) Cancer facts and figures). The American Cancer Society has estimated that, in the United States, approximately 40,000 women will die of breast cancer and about 16,000 will die of ovarian cancer in 2005. Surface epithelial tumors account for over 80% of all ovarian malignancies, which include serous tumors, mucinous tumors, endometrioid tumors and clear cell carcinomas (Seidman et al. “Blaustein's Pathology of the Female Genital Tract” 791-4 (Kurman, editor, 5th ed. New York, Springer-Verlag, 2002). Ovarian cancers frequently present at an advanced stage where metastatic disease has spread to regional and distant sites (Pettersson, (1994) Int. Fed. Of Gyn. and Obstetrics, Vol. 22; and Heintz et al. (2001) J. Epidermiol. Biostat. 6:107-38). Thus, while the lifetime probability of developing breast cancer is significantly higher than for ovarian cancer, the 5 year survival rate for breast cancer patients is substantially better than for those with ovarian cancer.
B7-like molecules belong to the immunoglobulin (Ig) superfamily. The extracellular portion of B7-like molecules contain single IgV and IgC domains and share ˜20%-40% amino acid identity. B7-like molecules play critical roles in the control and fine tuning of antigen-specific immune responses. O8E, known also as B7H4, B7x and B7S1, is a member of the B7 family and is thought to play a role in both stimulatory and inhibitory regulation of T cell responses (Carreno et al., (2002) Ann. Rev. Immunol. 20:29-53 and Khoury et al., (2004) Immunity 20:529-538). Human O8E has been mapped on chromosome 1 and is comprised of six exons and five introns spanning 66 kb, of which exon 6 is used for alternative splicing to generate two different transcripts (Choi et al. (2003) J. Immunol. 171:4650-4654).
O8E exerts its physiologic function by binding W a receptor on T cells, which in turn induces cell cycle arrest and inhibits the secretion of cytokines, the development of cytotoxicity and cytokine production of CD4+ and CD8+ T cells (Prasad et al. (2003) Immunity 18:863-873; Sica et al. (2003) Immunity 18:849-861; Wang et al. (2004) Microbes Infect. 6:759-66; and Zang et al. (2003) Proc. Natl. Acad. Sci. 100:10388-10392). It has been suggested that O8E may be an attenuator of inflammatory responses and may serve a role in down-regulation of antigen-specific immune and anti-tumor responses (Zang et al. (2003) Proc. Natl. Acad U.S.A. 100:10388-10392; Prasad et al. (2003) Immunity 18:863-873; Sica et al. (2003) Immunity 18:849-861; Choi et al. (2003) J. Immunol. 171:4650-4654; and Carreno et al. (2003) Trends Immunol. 24:524-7).
O8E mRNA but not protein expression has been detected in a wide range of normal somatic tissues, including liver, skeletal muscle, kidney, pancreas and small bowel (Sica et al. (2003) Immunity 18:849-61 and Choi et al. (2003) J. Immunol. 171:4650-4). O8E is inducible upon stimulation of T cells, B cells, monocytes and dendritic cells; however, immunohistochemistry analysis has revealed little expression in several peripheral tissues with the exception of positive staining in some ovarian and lung cancers (Id.). In addition, O8E is consistently overexpressed in primary and metastatic breast cancer, independent of tumor grade or stage, suggesting a critical role for this protein in breast cancer biology (Tringler et al. (2005) Clinical Cancer Res. 11:1842-48). See, also, U.S. Pat. Nos. 6,962,980; 6,699,664; 6,468,546; 6,488,931; 6,670,463; and 6,528,253, each of which is incorporated by reference herein in its entirety.
A wide variety of therapeutic modalities are available for the treatment of advanced breast and ovarian cancers including radiotherapy, conventional chemotherapy with cytotoxic antitumor agents, hormone therapy (aromatase inhibitors, luteinizing-hormone releasing-hormone analogues), bisphosphonates and signal-transduction inhibitors (Smith (2002) Lancet, 360:790-2). Unfortunately, however, many patients either respond poorly or not at all to any of these therapeutic modalities. Thus, there is a need to identify new molecular markers for and therapeutic agents against breast and ovarian cancers. Accordingly, O8E represents a valuable target for the treatment of cancers, including ovarian and breast cancers and a variety of other diseases characterized by O8E expression.